In this issue of the Journal, Ahn et al. (1) correlate an index of relative myocardial perfusion reserve (MPRI) by magnetic resonance imaging (MRI) in patients with aortic stenosis (AS) and angina pectoris, those with AS without angina, and control patients without aortic stenosis. The results confirm previously established inverse relationships of coronary flow reserve (CFR), severity of AS, and left ventricular (LV) hypertrophy (LVH) or mass. They sorted data into 3 groups in Figure 4 (1): patients with the most severe AS with angina, those with less severe AS without angina, and control subjects with no AS, LVH, or angina for the expected continuum of clinical AS in Figure 5. On the basis of the reduced mean MPRI in the AS-angina group, the authors conclude that microvascular dysfunction explains angina in severe AS.

Statistics Versus Physiology

Although the mean differences among the 3 groups are statistically significant, the data overlap is so great as to preclude predicting who gets angina in AS. Moreover, the wide scatter provides contravening physiological insights. Although no optimal cutoff of MPRI for angina is plotted, the data points plotted in Figure 4 (1) suggest that MPRI at a threshold of 0.9 identified only 60% of patients with angina, thereby leaving 40% failing to fit the microvascular hypothesis for angina in severe AS. Furthermore, ∼35% to 40% of asymptomatic patients had MPRI <0.9, again failing to fit the microvascular hypothesis.

Such great scatter with 35% to 40% of cases not fitting the microvascular hypothesis suggests another mechanism for angina in AS. As detailed in the following, previous literature indicates data that the authors may, or should, have to test the microvascular hypothesis. However, they did not report the critical data, perhaps due to their retrospective analysis rather than a hypothesis-testing design. Moreover, MPRI is a relative ratio of stress-to-rest upslope of the MRI signal. Therefore, lowered relative MPRI is likely due to increased resting perfusion associated with LVH and high-pressure workload than due to reduced stress perfusion. The “why angina in AS” is not new, as addressed in a series of papers and editorials since 1997 with cumulative data supporting a potentially definitive alternative answer reviewed in the following (2–11).

Coronary Physiology and Subendocardial Perfusion

Let us start with a brief review of coronary physiology before returning to the current MRI paper. Hyperemia of coronary blood flow follows every systole as a rapid increase in diastolic coronary blood flow after systolic compression, as illustrated in Figure 1(2). Experimentally, the rate of increase in coronary blood flow in early diastole is fastest in the epicardium and slowest in the subendocardium. The time delay in subendocardial after subepicardial hyperemia is significant, even for a normal heart with a 10- to 20-s delay in peak hyperemia in the 2 different myocardial layers. With tachycardia, the diastolic filling time is reduced, which would impair subendocardial perfusion in a normal heart, but subendocardium vasodilates further to maintain the rapid early diastolic hyperemia.

During reactive hyperemia after brief occlusion, the rapid rise and peak subendocardial perfusion is delayed by up to 10 seconds after the subepicardial rise and peal perfusion. Reduced diastolic perfusion time of tachycardia plus slow subendocardial perfusion may cause subendocardial perfusion and ischemia.

Many factors impede this rapid early diastolic hyperemia including segmental or diffuse coronary artery disease, hypotension, diastolic dysfunction, delayed diastolic relaxation, LVH, AS, sympathetic overdrive, localized coronary spasm, endothelial dysfunction, and rarely myocardial bridges, all separate and independent of microvascular disease. As these hemodynamics or pathophysiologies reduce the rapid early diastolic hyperemia, tachycardia shortens the diastolic perfusion time in direct proportion to heart rate. As the diastolic perfusion time shortens, there is not enough time between serial systoles for impeded, slowly increasing diastolic coronary blood flow to supply the subendocardium with adequate blood flow. Subendocardial ischemia ensues with angina and ST-segment depression on electrocardiography that are directly related to the dual interacting impediments to flow-shortened diastolic perfusion time and slowed early diastolic hyperemia. Therefore, reduced hyperemia or CFR is commonly due to hemodynamics that are not synonymous with microvascular disease.

Subendocardial Perfusion in AS

Although positron emission tomography (PET) imaging lacks the resolution of MRI, it has clarified myocardial perfusion in AS before and after aortic valve replacement (AVR) (3,4). In patients with severe AS undergoing quantitative PET perfusion imaging with dipyridamole stress, transmural CFR and the subendocardial-to-subepicardial perfusion ratio decrease directly with the decrease in hyperemic diastolic perfusion time (Figure 5 in Rajappan et al. [3]). Follow-up studies after AVR showed a direct relationship between improved CFR, increased hyperemic diastolic perfusion time, and increased aortic valve area (4). The relationship of CFR and the subendocardial-to-subepicardial perfusion ratio to the hyperemic diastolic perfusion time before and after AVR indicates that hemodynamic conditions determine CFR, not microvascular disease. Microvascular disease would be expected to reduce perfusion uniformly throughout the LV wall and remain fixed transmurally without a subendocardial-subepicardial perfusion gradient that is directly related to diastolic perfusion time.

Invasive Hemodynamics Before and After Percutaneous AVR

In patients with angina and severe AS, invasive pressures and flow velocities have been measured before and after percutaneous AVR. The impaired CFR before valve replacement immediately normalizes after AVR with immediate relief of angina. This observation indicates that the impaired CFR and angina are due to hemodynamic factors with immediate normalization of CFR and relief of angina when the hemodynamic factors were corrected. These observations rule against microvascular dysfunction as causing the reduced CFR and angina because microvascular disease would not correlate so closely with hemodynamic factors or normalize immediately after valve replacement (8).

The gold standard for microvascular dysfunction is coronary vascular bed resistance from invasive pressure and flow velocity measurements during vasodilator hyperemia (9). Therefore, one might ask whether perfusion alone can uniquely define microvascular dysfunction. On the basis of coronary physiology, there is an observation on perfusion alone that should differentiate pure isolated microvascular disease from other causes that reduce hyperemic perfusion or CFR. The clue is absolute subendocardial and subepicardial perfusion and their ratio. Microvascular disease should be uniform throughout the LV wall and uniformly reduce transmural myocardial perfusion reserve without a subendocardial-to-subepicardial perfusion gradient. In contrast, all other pathophysiologies reducing hyperemic perfusion or CFR cause an abnormally low subendocardial-to-subepicardial perfusion ratio with absolute reduction in subendocardial perfusion to ischemic low-flow levels associated with angina and electrocardiographic changes.

Instructive Errors of Omission

With current literature as the basis for a potentially definitive MRI study, do the data in the current paper resolve the mechanism of angina in AS? The essential fundamental data not reported are hyperemic heart rate, blood pressure, diastolic perfusion time, subendocardial and subepicardial perfusion in milliliters/minute/gram, their ratio, and absolute CFR. In the literature, these data explained reduced stress flow, CFR, angina, and their normalization with relief of angina after valve replacement. Perhaps their omission derives from the retrospective analysis as opposed to hypothesis-testing design.

Therefore, the conclusion that microvascular disease causes angina in AS is simply not related to reduced MPRI because no data on the hemodynamic or microvascular mechanisms are reported. Although the references acknowledge some of the literature on the topic, the lesson of “let the data talk” (5–7) seems to have gotten lost in a retrospective analysis to support a preconceived notion rather than measuring data designed to challenge the hypothesis as true or not.

The “MRI Silo” of Expertise

The complexity of cardiovascular medicine, e.g., imaging, interventions, prevention, medical management, is so great that expertise derives from highly focused skills, thinking, and reading. The resulting “silos of expertise” are understandable but carry great risk of isolation from fundamental clinical coronary physiology. This incomplete paper by clearly experts in the “MRI silo” overlooks essential physiology in the literature, perhaps what a skeptic might call a “physiology silo.” However, the latter is basic to life, whereas the former is a technology intended to see truths in the physiological silo of life.

Nature is a complex of processes and truths that care little about our mental silos and preconceptions from which we view nature. Our task as medical scientists is not dedication to a methodology “silo” but to use that silo of expertise to see nature’s truths, to let the data talk to us, and to tell us nature’s truths for improving our patients lives.

With this paper and editorial as a springboard, perhaps another carefully designed MRI study will measure diastolic perfusion time, hyperemic blood pressure and heart rate, rest and hyperemic subendocardial and subepicardial perfusion in milliliters/minute/gram, their ratio, and absolute CFR. Such definitive physiological data would then be the classic paper on angina in AS that would lay to rest this old question, perhaps worthy of a final editorial integrating the technology of myocardial perfusion imaging with clinical coronary physiology across different silos of expertise.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

Dr. Gould received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis and is the 510(k) applicant for CFR Quant (K113754) and HeartSee (K143664), for software for quantifying absolute flow using cardiac positron emission tomography and analysis, including absolute flow quantification. Dr. Johnson receives internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis and significant institutional research support from St. Jude Medical (for CONTRAST, NCT02184117) and Volcano/Philips Corporation (for DEFINE-FLOW, NCT02328820), makers of intracoronary pressure and flow sensors.

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